The present invention is concerned with novel quinoline derivatives useful as neuropeptide Y (NPY) receptor ligands, particularly neuropeptide Y (NPY) antagonists.
The subject invention provides compounds of formula: 
wherein:
R1 is hydrogen, alkyl, alkoxyalkyl, alkenyl, alkinyl, hydroxyalkyl, aralkyl, heterocyclylalkyl, cycloalkylalkyl, NH2xe2x80x94SO2xe2x80x94, monoalkylamino-SO2xe2x80x94, dialkylamino-SO2xe2x80x94, alkyl-SO2xe2x80x94, aryl, NH2-alkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aryl-SO2xe2x80x94O-alkyl, cycloalkyl, or cycloalkylalkyl;
R2 is hydrogen, halogen, alkyl, alkenyl, alkinyl, aralkyl, heteroarylalkyl, hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl, aryloxy, arylamino, heteroarylamino, NH2xe2x80x94, monoalkylamino, dialkylamino, heterocyclyl, arylalkylamino, heteroarylalkylamino, aryl, arylalkoxy, or heteroarylalkoxy;
R3 is hydrogen, alkyl, NH2xe2x80x94, monoalkylamino, dialkylamino, or alkoxy;
R4 is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, NH2xe2x80x94, monoalkylamino, dialkylamino, acetylamino, cyano, hydroxyalkyl, alkoxyalkyl, cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclyl, heterocyclyloxy, heterocyclyloxyalkoxy, hydroxyalkoxy, alkoxycarbonyl, carboxy, heterocyclylalkyl, alkyl-SO2xe2x80x94, or aryl-SO2xe2x80x94;
R5 is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, NH2xe2x80x94, monoalkylamino, dialkylamino, acetylamino, cyano, hydroxyalkyl, alkoxyalkyl, cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclyl, heterocyclyloxy, heterocyclyloxyalkoxy, hydroxyalkoxy, alkoxycarbonyl, carboxy, heterocyclylalkyl, alkyl-SO2xe2x80x94, or aryl-SO2xe2x80x94;
A is a 5- to 10-membered mono- or bicyclic saturated heterocyclic ring comprising the nitrogen atom which is attached to the quinoline ring or a 5- to 10-membered mono- or bicyclic saturated heterocyclic ring comprising the nitrogen atom which is attached to the quinoline ring, which is substituted by one or two further heteroatoms which are independently selected from the group consisting or oxygen, sulfur and nitrogen;
and pharmaceutically acceptable salts or esters thereof.
A preferred embodiment is where R1 is hydrogen, alkyl, alkoxyalkyl, alkenyl, alkinyl, hydroxyalkyl, aralkyl, heterocyclylalkyl, cycloalkylalkyl, NH2xe2x80x94SO2xe2x80x94, monoalkylamino-SO2xe2x80x94, dialkylamino-SO2xe2x80x94, or alkyl-SO2xe2x80x94; R4 is hydrogen, alkyl, alkoxy, hydroxy, NH2xe2x80x94, monoalkylamino, dialkylamino, acetylamino, or cyano; R5 is hydrogen; and A is a saturated ring consisting of the nitrogen atom which is attached to the quinoline ring and a xe2x80x94(CH2)nxe2x80x94 moiety with n being 4, 5, or 6. Preferred compounds are where R1 is hydrogen, cycloalkylalkyl, aralkyl, or heteroarylalkyl. Further preferred compounds are where R1 is hydrogen, aralkyl or heteroarylalkyl, favorably hydrogen, phenylalkyl, pyridinylalkyl, phenylalkyl wherein the phenyl cycle is substituted by one to three substituents independently selected from the group consisting of alkoxy, cyano and halogen, and pyridinylalkyl wherein the pyridinyl cycle is substituted by one to three substituents independently selected from the group consisting of alkoxy, cyano and halogen. Especially preferred is where R1 is hydrogen, cyclopropylmethyl, (methoxyphenyl) methyl, (cyanophenyl) methyl, (chlorophenyl) methyl, pyridinylmethyl, chloropyridinylmethyl, or fluoropyridinylmethyl.
Favored groups of compounds are where R2 is hydrogen, alkyl or halogen. Especially preferred is where R2 is hydrogen, butyl, fluoro, chloro or bromo.
R3 is favorably hydrogen, alkyl, or NH2xe2x80x94. Methyl is a preferred alkyl group.
R4 is favorably hydrogen, alkoxy, alkoxyalkyl, hydroxyalkyl or hydroxy. A is preferably a pyrrolidinyl or azepanyl ring, with the pyrrolidinyl ring being favored.
The subject invention also provides compounds of formula: 
wherein:
R1xe2x80x2 is hydrogen, phenylalkyl, pyridinylalkyl, phenylalkyl wherein the phenyl cycle is substituted by a substituent selected from the group consisting of alkoxy, cyano and halogen, and pyridinylalkyl wherein the pyridinyl cycle is substituted by a substituent selected from the group consisting of alkoxy, cyano and halogen;
R2xe2x80x2 is is hydrogen, alkyl or halogen;
R3xe2x80x2 is hydrogen or alkyl;
Axe2x80x2 is selected from the group consisting of pyrrolidinyl, pyrrolidinyl substituted by hydroxy, alkyloxy, hydroxyalkyl or alkyloxyalkyl, and azepanyl;
and pharmaceutically acceptable salts and esters thereof.
Some favored compounds are where R3xe2x80x2 is hydrogen or methyl, Axe2x80x2 is pyrrolidinyl, R2xe2x80x2 is alkyl, such as butyl, and R1xe2x80x2 is hydrogen, e.g. 6-butyl-4-pyrrolidin-1-yl-quinolin-7-ol or a pharmaceutically acceptable salt or ester thereof R1xe2x80x2 may also be (cyanophenyl)methyl, e.g. 4-(6-butyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile or a pharmaceutically acceptable salt or ester thereof
Other favored compounds are where R3xe2x80x2 is methyl, Axe2x80x2 is azepanyl, R2xe2x80x2 is hydrogen, and R1xe2x80x2 is pyridinylmethyl, e.g. 4-azepan-1-yl-2-methyl-7-(pyridin-4-ylmethoxy)-quinoline or a pharmaceutically acceptable salt or ester thereof. R1xe2x80x2 may also be (cyanophenyl)methy, e.g. 4-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile or 3-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile or a pharmaceutically acceptable salts or esters thereof.
Preferred compounds include those where Axe2x80x2 is pyrrolidinyl or pyrrolidinyl which is substituted by hydroxy, alkyloxy, hydroxyalkyl or alkyloxyalkyl. A favored group is where Axe2x80x2 is pyrrolidinyl, R2xe2x80x2 is hydrogen or halogen. R1xe2x80x2 can favorably-be hydrogen, phenylalkyl wherein the phenyl cycle is substituted by a substituent selected from the group consisting of alkoxy, cyano and halogen, and pyridinylalkyl wherein the pyridinyl cycle is substituted by a substituent selected from the group consisting of alkoxy, cyano and halogen. When R1xe2x80x2 is hydrogen, 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol or a pharmaceutically acceptable salt or ester thereof is favored. When R1xe2x80x2 is (methoxyphenyl)methyl, 7-(3-methoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline and pharmaceutically acceptable salts and esters thereof is favored. When R1xe2x80x2 is (cyanophenyl)methyl, 2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl) -benzonitrile and 4-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile, as well as pharmaceutically acceptable salts and esters thereof are favored. Where R1xe2x80x2 is (chlorophenyl)methyl, 7-(3-chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline and 7-(4-chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline, as well as pharmaceutically acceptable salts and esters thereof are preferred. R1xe2x80x2 is (chloropyridinyl)methyl, 7-(2-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline and pharmaceutically acceptable salts and esters thereof are favored. When R2xe2x80x2 is halogen, such as fluoro, and R1xe2x80x2 is (cyanophenyl)methyl, the comopund 4-(6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)benzonitrile and pharmaceutically acceptable salts and esters thereof are preferred. Likewise, when R1xe2x80x2 is (fluoropyridinyl)methyl, 6-fluoro-7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline and pharmaceutically acceptable salts and esters thereof are preferred and when Rxe2x80x2 is (chloropyridinyl)methyl, 7-(2-chloro-pyridin-3-ylmethoxy)-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinoline and pharmaceutically acceptable salts and esters thereof are preferred.
Preferred compounds also include those where Axe2x80x2 is pyrrolidinyl which is substituted by hydroxy, alkyloxy, hydroxyalkyl or alkyloxyalkyl. When Axe2x80x2 is pyrrolidinyl which is substituted by hydroxy, R1xe2x80x2 is (cyanophenyl)methyl, and R2xe2x80x2 is hydrogen, the compounds (S) and (R)-4-[4-(3-hydroxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile and pharmaceutically acceptable salts and esters thereof are favored. When Axe2x80x2 is pyrrolidinyl which is substituted by alkyloxy, such as methoxy, and R1xe2x80x2 is (cyanophenyl)methyl, the compound (S)-4-[4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile and pharmaceutically acceptable salts and esters thereof are preferred. If Axe2x80x2 is pyrrolidinyl which is substituted by ethoxy, R2xe2x80x2 is hydrogen, and R1xe2x80x2 is (cyanophenyl)methyl, then (S)-4-[4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile or a pharmaceutically acceptable salt or ester thereof is favored. If R1xe2x80x2 is (fluoropyridinyl)methyl, then (S) 4-(3-ethoxy-pyrrolidin-1-yl)-7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-quinoline or a pharmaceutically acceptable salt or ester thereof is favored. If R1xe2x80x2 is (chloropyridinyl)methyl, then (S) 7-(2-chloro-pyridin-3-ylmethoxy)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinoline or a pharmaceutically acceptable salt or ester thereof is favored.
When Axe2x80x2 is pyrrolidinyl which is substituted by hydroxyalkyl, e.g. hydroxymethyl, R2xe2x80x2 is hydrogen, and R1xe2x80x2 is (fluoropyridinyl)methyl, then (S)-{1-[7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-quinolin-4-yl]-pyrrolidin-2-yl}-methanol or a pharmaceutically acceptable salt or ester thereof is the favored compound. If R1xe2x80x2 is (chloropyridinyl)methyl, then the preferred compound is (S)-{1-[7-(2-chloro-pyridin-3-ylmethoxy)-2-methyl-quinolin-4-yl]-pyrrolidin-2-yl}-methanol or a pharmaceutically acceptable salt or ester thereof, and if R1xe2x80x2 is (cyanophenyl)methy, then the preferred compound is (S) or (R)-4-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile or a pharmaceutically acceptable salt or ester thereof.
Other favored compounds are where R2xe2x80x2 is halogen, e.g. fluoro, and R1xe2x80x2 is (cyanophenyl)methyl, for example (S)-4-[6-fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile or a pharmaceutically acceptable salt or ester thereof. If Axe2x80x2 is pyrrolidinyl which is substituted by alkyloxyalkyl, such as methoxymethyl, and R2xe2x80x2 is hydrogen, and R1xe2x80x2 is (fluoropyridinyl)methyl, then the favored compound is (S)-7-(2-fluoro-pyridin-3-ylmethoxy)-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinoline or a pharmaceutically acceptable salt or ester thereof. Should R1xe2x80x2 be (chloropyridinyl)methyl, then (S)-7-(2-chloro-pyridin-3-ylmethoxy)-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinoline or a pharmaceutically acceptable salt or ester thereof would be the favored compound.
For brevity, each and every combination of substituents has not been listed individually. However, it is intended that each and every combination of substituents be considered described and enabled by the present specification.